Hepatocyte Estrogen Receptor α Mediates Estrogen-induced Augmentation of Hepatic Mitochondrial Respiration Following Ovariectomy

Whole-body estrogen receptor α (ERα) knockout mice develop hepatic steatosis; however, liver-specific loss of ERα (LERKO) mice fails to recapitulate this phenotype in female mice, coinciding with the maintenance of normal hepatic mitochondrial function. Despite this, estrogen-mediated protection against hepatic steatosis is lost in LERKO mice following ovariectomy (OVX). Here, we tested if loss of hepatic ERα blunts estrogen-modulation of hepatic mitochondrial respiratory capacity following OVX. Sham or OVX surgery was performed in middle-aged female mice (36-40 weeks), immediately followed by AAV injection to generate Control (Con; GFP) or LERKO mice (Cre). All mice were placed on a high-fat diet (HFD) for 10 weeks following the initial surgery. Half of the OVX mice received 17β-estradiol (E2) replacement (OVX+E2) for the last 4 weeks of dietary intervention. OVX mice possessed greater body mass and adiposity compared to Sham, which was reversed by E2 replacement in both Con and LERKO mice. While E2 replacement reduced steatosis in both Con and LERKO OVX mice, LERKO OVX mice possessed overall greater intrahepatic triglyceride content. Under palmitate-supported respiratory conditions, E2 replacement stimulated greater basal and ADP-stimulated (State 3) mitochondrial respiration only in Con OVX mice. However, this E2-mediated augmentation of mitochondrial respiration occurred despite no discernable differences in the modulation of mitochondrial respiration in response to changes in energy demand (ΔG ATP ). In both Con and LERKO OVX mice, E2 replacement drastically reduced mitochondrial-derived H 2 O 2 production and maximal branched-chain keto acid (BCKA)-supported mitochondrial respiration. In conclusion, following the loss of ovarian function, estrogen is capable of restoring protection against hepatic steatosis; however, E2-mediated enhancements to hepatic mitochondrial respiratory capacity require hepatic ERα. This study was supported by VA Merit Review grant 1I01BX002567 (JPT), NIH P20GM144269 (CSM, EMM, JPT), NIH T32DK128770 (EF, SFS) and NIH T32AG07811 (BAK). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.